Penile squamous cell carcinoma (pSCC) represents an uncommon malignancy characterized by stagnant mortality, psychosexual distress, and a highly variable prognosis. Currently, the World Health Organization distinguishes between human papillomavirus (HPV)-related and HPV-independent pSCC. Recently, there has been an evolving line of research documenting the enrichment of HPV-independent pSCC with a high tumor mutational burden (TMB) and programmed death ligand-1 expression, as well as clusters of genes associated with HPV status. In this study, we conducted comprehensive next-generation sequencing DNA profiling of 146 pSCC samples using a panel consisting of 355 genes associated with tumors. This profiling was correlated with immunohistochemical markers and prognostic clinical data. A survival analysis of recurrent genomic events (found in ≥10 cases) was performed. TP53, CDKN2A, ATM, EPHA7, POT1, CHEK1, GRIN2A, and EGFR alterations were associated with significantly shortened overall survival in univariate and multivariate analysis. HPV positivity, diagnosed through both p16 immunohistochemistry and HPV DNA analysis, displayed no impact on survival but was associated with high-grade, lymphatic invasion, programmed death ligand-1 negativity/weak expression, and low TMB. FAT1, TP53, CDKN2A, CASP8, and HRAS were more often mutated in HPV-independent pSCC. In contrast, HPV-associated pSCCs were enriched by EPHA7, ATM, GRIN2A, and CHEK1 mutations. PIK3CA, FAT1, FBXW7, and KMT2D mutations were associated with high TMB. NOTCH1, TP53, CDKN2A, POT1, KMT2D, ATM, CHEK1, EPHA3, and EGFR alterations were related to adverse clinicopathologic signs, such as advanced stage, high tumor budding, and lymphovascular invasion. We detected 160 alterations with potential treatment implications, with 21.2% of samples showing alterations in the homologous recombination repair pathway. To the best of our knowledge, this study describes the largest cohort of pSCC with complex molecular pathologic, clinical, and prognostic analysis correlating with prognosis.

• MeSH
• Ataxia Telangiectasia Mutated Proteins genetics   MeSH
• Adult MeSH
• ErbB Receptors genetics   MeSH
• Papillomavirus Infections MeSH
• Cyclin-Dependent Kinase Inhibitor p16 genetics   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation MeSH
• Biomarkers, Tumor * genetics   analysis   MeSH
• Tumor Suppressor Protein p53 genetics   MeSH
• Penile Neoplasms * genetics   mortality   pathology   virology   MeSH
• Prognosis MeSH
• Telomere-Binding Proteins MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Shelterin Complex MeSH
• Carcinoma, Squamous Cell * genetics   mortality   pathology   virology   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: A multicomponent meningococcal serogroups ABCWY vaccine (MenABCWY) could provide broad protection against disease-causing meningococcal strains and simplify the immunisation schedule. The aim of this trial was to confirm the effect of the licensed meningococcal serogroup B (MenB) vaccine, 4CMenB, against diverse MenB strains, and to assess the breadth of immune response against a panel of 110 MenB strains for MenABCWY containing the antigenic components of 4CMenB and licensed serogroups ACWY vaccine, MenACWY-CRM, the non-inferiority of the immune response with MenABCWY versus 4CMenB and MenACWY-CRM, safety, and MenABCWY lot-to-lot consistency. METHODS: We conducted a phase 3 randomised, controlled, observer-blinded trial of healthy adolescents and young adults (age 10-25 years) across 114 centres in Australia, Canada, Czechia, Estonia, Finland, Türkiye, and the USA. Exclusion criteria included previous vaccination with a MenB vaccine or (within the last 4 years) MenACWY vaccine. Participants were randomly allocated (5:5:3:3:3:1 ratio) via a central randomisation system using a minimisation procedure to receive 4CMenB at months 0, 2, and 6 (referred to as 4CMenB 0-2-6 hereafter); or 4CMenB at months 0 and 6 (referred to as 4CMenB 0-6 hereafter); or MenABCWY (three groups, each receiving one production lot of the MenACWY-CRM component) at months 0 and 6; or MenACWY-CRM at month 0. Demonstration in the per-protocol set of the consistency of three MenACWY-CRM component lots of the MenABCWY vaccine was a primary objective (demonstrated with two-sided 95% CIs for the ratio of human serum bactericidal antibody [hSBA] geometric mean titres against each serogroup within predefined criteria [0·5-2·0]). The primary endpoints (breadth of immune response) for the MenB component of MenABCWY and 4CMenB were measured using the endogenous complement hSBA (enc-hSBA) assay against a panel of 110 diverse MenB invasive disease strains. For each serum sample, 35 strains from the 110 MenB strain panel were randomly selected for testing. The 4CMenB breadth of immune response data have been published separately. For MenABCWY, breadth of immune response was assessed in two analyses: a test-based analysis of the percentage of samples (tests) without bactericidal serum activity against MenB strains 1 month after two MenABCWY doses versus the percentage after one MenACWY-CRM dose in the per-protocol set, and a responder-based analysis of the percentage of participants (responders) whose sera killed 70% or more strains at 1 month after two MenABCWY doses in the full analysis set. A lower limit of two-sided 95% CI above 65% would demonstrate breadth of immune response. Other primary outcomes included non-inferiority (5% margin) of two MenABCWY doses versus two 4CMenB doses by enc-hSBA assay in the per-protocol set, non-inferiority (10% margin) of two MenABCWY doses versus one MenACWY-CRM dose in MenACWY vaccine-naive participants by traditional hSBA assay in the per-protocol set, and safety in all vaccinated participants. This trial is registered with ClinicalTrials.gov, NCT04502693, and is complete. FINDINGS: Between Aug 14, 2020, and Sept 3, 2021, 3651 participants were enrolled and randomly allocated (900 in the 4CMenB 0-2-6 group and 908 in the 4CMenB 0-6 group, 1666 in the three MenABCWY groups combined, and 177 in the MenACWY-CRM group). All primary objectives for MenABCWY were met. Consistency of immune responses against the three production lots of the MenACWY component of MenABCWY was demonstrated since two-sided 95% CIs for the ratios of hSBA geometric mean titres against serogroups A, C, W, and Y for each pair of lots were within the predefined equivalence criteria. The lot data were pooled for the remainder of MenABCWY endpoints. By enc-hSBA assay, breadth of immune response against the MenB strain panel was 77·9% (95% CI 76·6 to 79·2) in the test-based analysis and 84·1% (81·4 to 86·5; 687 of 817 participants) in the responder-based analysis. Non-inferiority of MenABCWY to 4CMenB was demonstrated by enc-hSBA assay: the difference in percentage of samples with bactericidal serum activity between the MenABCWY group (82·5% [95% CI 82·1 to 83·0]; 21 222 of 25 715) and 4CMenB 0-2 group (83·1% [82·7 to 83·6]; 22 921 of 27 569) was -0·61% (-1·25 to 0·03). Non-inferiority of two-dose MenABCWY to one-dose MenACWY-CRM was demonstrated by traditional hSBA assay, with differences between the MenABCWY group and MenACWY group in percentages of participants with a four-fold rise in hSBA titres of 11·3% (5·9 to 19·0) for serogroup A, 47·2% (38·1 to 56·3) for serogroup C, 35·3% (26·9 to 44·5) for serogroup W, and 27·0% (19·4 to 35·8) for serogroup Y. MenABCWY reactogenicity was mostly of mild or moderate severity and transient, with similar frequencies of adverse events in the MenABCWY and 4CMenB groups and no safety concerns were identified. INTERPRETATION: This study demonstrates breadth of immune response against a panel of 110 MenB strains for the MenB component of the investigational MenABCWY vaccine, when administered as a 0-6 months schedule to the target population of adolescents and young adults, with predefined criteria for success met for both breadth of immune response endpoints and for non-inferiority versus 4CMenB. This investigational vaccine could provide broad meningococcal serogroup coverage in a simplified immunisation schedule, thus aiding the public health attempt in preventing invasive meningococcal disease due to five Neisseria meningitidis serogroups in adolescents and young adults. FUNDING: GSK.

• MeSH
• Child MeSH
• Adult MeSH
• Immunogenicity, Vaccine * MeSH
• Single-Blind Method MeSH
• Humans MeSH
• Meningococcal Infections * prevention & control   immunology   MeSH
• Meningococcal Vaccines * immunology   adverse effects   administration & dosage   MeSH
• Adolescent MeSH
• Young Adult MeSH
• Neisseria meningitidis, Serogroup B immunology   MeSH
• Neisseria meningitidis immunology   MeSH
• Antibodies, Bacterial blood   MeSH
• Healthy Volunteers MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Equivalence Trial MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH

OBJECTIVES: To prospectively validate the diagnostic performance of a non-invasive point-of-care tool (Rapid IAI System), including vaginal alpha-fetoprotein and interleukin-6, to predict the occurrence of intra-amniotic inflammation in a Spanish cohort of patients admitted with a diagnosis of preterm labor and intact membranes. METHODS: From 2017 to 2022, we prospectively evaluated a cohort of pregnant women diagnosed with preterm labor and intact membranes admitted below 34+0 weeks who underwent amniocentesis to rule-in/out intra-amniotic infection and/or inflammation. Vaginal sampling was performed at the time of amniocentesis or within 24-48 h. Amniotic fluid IL-6, vaginal alpha-fetoprotein and vaginal IL-6 concentrations were measured using a point-of-care tool provided by Hologic Inc., "Rapid IAI System". We defined intra-amniotic inflammation when amniotic fluid IL-6 values were greater than 11.3 ng/mL. During recruitment, clinicians were blinded to the results of the point-of-care tool. The original prediction model proposed by Hologic Inc. to predict intra-amniotic inflammation was validated in this cohort of patients. RESULTS: We included 151 patients diagnosed with preterm labor and intact membranes. Among these, 29 (19.2 %) had intra-amniotic inflammation. The algorithm including vaginal IL-6 and alpha-fetoprotein showed an area under curve to predict intra-amniotic inflammation of 80.3 % (±5.3 %) with a sensitivity of 72.4 %, specificity of 84.6 %, positive predictive valuve (PPV) of 52.5 %, negative predictive value (NPV) of 92.9 %, and a positive likelihood ratio (LR+) of 4.6 and negative likelihood ratio (LR-) of 0.33. CONCLUSIONS: External validation of a non-invasive rapid point-of-care tool, including vaginal alpha-fetoprotein and IL-6, showed very good diagnostic performance for predicting the absence of intra-amniotic inflammation in women with preterm labor and intact membranes.

• MeSH
• alpha-Fetoproteins * analysis   metabolism   MeSH
• Amniocentesis methods   MeSH
• Chorioamnionitis * diagnosis   MeSH
• Adult MeSH
• Risk Assessment methods   MeSH
• Interleukin-6 * analysis   blood   metabolism   MeSH
• Humans MeSH
• Amniotic Fluid * metabolism   chemistry   MeSH
• Point-of-Care Testing MeSH
• Obstetric Labor, Premature * diagnosis   MeSH
• Predictive Value of Tests MeSH
• Prospective Studies MeSH
• Pregnancy MeSH
• Vagina metabolism   MeSH
• Point-of-Care Systems MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Validation Study MeSH

INTRODUCTION: Breast cancer comprises the leading cause of cancer-related death in women. MicroRNAs (miRNAs) have emerged as important factors with concern to carcinogenesis and have potential for use as biomarkers. METHODS: This study provides a comprehensive evaluation of the microRNA expression in invasive breast carcinoma of no special type tissues compared with benign tissues via large-scale screening and the candidate-specific validation of 15 miRNAs and U6 snRNA applying qPCR and the examination of clinicopathological data. RESULTS: Of the six downregulated miRNAs, let-7c was identified as the most promising miRNA biomarker and its lower expression was linked with Ki-67 positivity, luminal B versus luminal A samples, multifocality, lymph node metastasis, and inferior PFS. Of the 9 upregulated sncRNAs, the data on U6 snRNA, miR-493 and miR-454 highlighted their potential oncogenic functions. An elevated U6 snRNA expression was associated with the tumor grade, Ki-67 positivity, luminal B versus A samples, lymph node metastasis, and worsened PFS (and OS) outcomes. An elevated miR-454 expression was detected in higher grades, Ki-67 positive and luminal B versus A samples. Higher miR-493 levels were noted for the tumor stage (and grade) and worse patient outcomes (PFS, OS). The data also suggested that miR-451a and miR-328 may have tumor suppressor roles, and miR-182 and miR-200c pro-oncogenic functions, while the remaining sncRNAs did not evince any significant associations. CONCLUSION: We showed particular microRNAs and U6 snRNA as differentially expressed between tumors and benign tissues and associated with clinicopathological parameters, thus potentially corresponding with important roles in breast carcinogenesis. Their importance should be further investigated and evaluated in follow-up studies to reveal their potential in clinical practice. INTRODUCTION: Breast cancer comprises the leading cause of cancer-related death in women. MicroRNAs (miRNAs) have emerged as important factors with concern to carcinogenesis and have potential for use as biomarkers. METHODS: This study provides a comprehensive evaluation of the microRNA expression in invasive breast carcinoma of no special type tissues compared with benign tissues via large-scale screening and the candidate-specific validation of 15 miRNAs and U6 snRNA applying qPCR and the examination of clinicopathological data. RESULTS: Of the six downregulated miRNAs, let-7c was identified as the most promising miRNA biomarker and its lower expression was linked with Ki-67 positivity, luminal B versus luminal A samples, multifocality, lymph node metastasis, and inferior PFS. Of the 9 upregulated sncRNAs, the data on U6 snRNA, miR-493 and miR-454 highlighted their potential oncogenic functions. An elevated U6 snRNA expression was associated with the tumor grade, Ki-67 positivity, luminal B versus A samples, lymph node metastasis, and worsened PFS (and OS) outcomes. An elevated miR-454 expression was detected in higher grades, Ki-67 positive and luminal B versus A samples. Higher miR-493 levels were noted for the tumor stage (and grade) and worse patient outcomes (PFS, OS). The data also suggested that miR-451a and miR-328 may have tumor suppressor roles, and miR-182 and miR-200c pro-oncogenic functions, while the remaining sncRNAs did not evince any significant associations. CONCLUSION: We showed particular microRNAs and U6 snRNA as differentially expressed between tumors and benign tissues and associated with clinicopathological parameters, thus potentially corresponding with important roles in breast carcinogenesis. Their importance should be further investigated and evaluated in follow-up studies to reveal their potential in clinical practice.

• MeSH
• Adult MeSH
• Neoplasm Invasiveness MeSH
• Middle Aged MeSH
• Humans MeSH
• Lymphatic Metastasis MeSH
• MicroRNAs * genetics   metabolism   MeSH
• Biomarkers, Tumor * genetics   metabolism   MeSH
• Breast Neoplasms * pathology   genetics   metabolism   mortality   MeSH
• Gene Expression Regulation, Neoplastic * MeSH
• RNA, Small Nuclear * genetics   metabolism   MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Emerging evidence suggests that tumour morphological heterogeneity may influence mutational profiles relevant to therapy response. In this pilot study, we aimed to assess whether mutations identified within specific morphological patterns or at the invasion front correlate with shorter time to progression after anti-EGFR therapy, as compared to whole-tissue analysis. METHODS: We investigated genetic mutations in 142 samples from primary tumours of 39 KRAS wild-type metastatic colorectal cancer (CRC) patients receiving anti-EGFR therapy. Deep next-generation sequencing was performed on whole-tumour sections and six morphology-defined tumour regions. RESULTS: Mutations in genes linked to anti-EGFR therapy response (KRAS, BRAF, NRAS, PTEN and PI3KCA) were found uniquely in the non-responder group, with substantial variability across morphological sub-regions. BRAF mutations were aligned with serrated and mucinous morphologies, while KRAS mutations (p.Lys147Glu and p.Ala146Thr) were associated with mucinous and desmoplastic morphologies. In all cases, the cumulative mutational profile from sub-regions provided more details than that of the whole-tumour profile. CONCLUSION: Our findings highlight that comprehensive analysis, considering morphological heterogeneity, is crucial for personalised CRC treatment strategies.

• MeSH
• Drug Resistance, Neoplasm * genetics   MeSH
• Adult MeSH
• ErbB Receptors antagonists & inhibitors   MeSH
• PTEN Phosphohydrolase genetics   MeSH
• GTP Phosphohydrolases genetics   MeSH
• Protein Kinase Inhibitors * therapeutic use   MeSH
• Colorectal Neoplasms * genetics   drug therapy   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation * MeSH
• DNA Mutational Analysis MeSH
• Pilot Projects MeSH
• Antineoplastic Agents * therapeutic use   MeSH
• Proto-Oncogene Proteins B-raf genetics   MeSH
• Proto-Oncogene Proteins p21(ras) genetics   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• High-Throughput Nucleotide Sequencing MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Conflict deeply affects human experiences, frequently testing individual resilience to its breaking point and leaving enduring psychological and societal wounds. The current conflict in Ukraine, initiated by Russia's invasion in 2022, illustrates this phenomenon by altering regional relationships and triggering a major humanitarian crisis marked by extensive displacement, loss of life, and emotional turmoil. This study explores the factors influencing hope and distress in Ukraine alongside six nearby European countries during the ongoing conflict. A cross-sectional survey collected data primarily via internet panel samples from the Czech Republic, Georgia, Lithuania, Poland, Romania, Slovakia, and Ukraine in the second year since the war's initiation. The current study utilised validated instruments, collecting data on levels of hope, distress, individual resilience, community resilience, societal resilience, morale, sense of danger, perceived security threats, and demographic characteristics. Hope and distress levels differ across countries, with Ukraine exhibiting the highest levels of both (3.74 ± 1.02 and 2.89 ± 0.87, respectively). Overall, average scores of hope were higher than average distress levels. Across the regression models for the seven countries, hope showed strong associations with individual (between β = 0.089 and β = 0.327) and societal resilience (between β = 0.206 and β = 0.514), while morale (between β = -0.104 and β = -0.479) and individual resilience (between β = -0.077 and β = -0.335) displayed a protective relationship against distress (all β values were significant, p < 0.01). Monitoring hope and distress is crucial during the Russian-Ukrainian war and other adversities, as these factors give insight into the current and future psychological states of affected populations. The results offer valuable information that can guide the development of tailored strategies to enhance hope and buffer distress in war-impacted countries, as well as those experiencing its broader effects. Fostering individual and societal resilience, alongside enhancing morale, may strengthen hope and mitigate distress amid adversity. Developing targeted interventions that address each population's unique needs, as well as their sociocultural and geopolitical contexts can enhance efficacy.

• MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Hope * MeSH
• Armed Conflicts * psychology   MeSH
• Cross-Sectional Studies MeSH
• Resilience, Psychological * MeSH
• Psychological Distress * MeSH
• Stress, Psychological * psychology   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Russia MeSH
• Ukraine MeSH

INTRODUCTION: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) may be as high as 38% in the adult population with potential serious complications, multiple comorbidities and a high socioeconomic burden. However, there is a general lack of awareness and knowledge about MASLD and its progressive stages (metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis). Therefore, MASLD is still far underdiagnosed. The 'Global Research Initiative for Patient Screening on MASH' (GRIPonMASH) consortium focuses on this unmet public health need. GRIPonMASH will help (primary) healthcare providers to implement a patient care pathway, as recommended by multiple scientific societies, to identify patients at risk of severe MASLD and to raise awareness. Furthermore, GRIPonMASH will contribute to a better understanding of the pathophysiology of MASLD and improved identification of diagnostic and prognostic markers to detect individuals at risk. METHODS: This is a prospective multicentre observational study in which 10 000 high-risk patients (type 2 diabetes mellitus, obesity, metabolic syndrome or hypertension) will be screened in 10 European countries using at least two non-invasive tests (Fibrosis-4 index and FibroScan). Blood samples and liver biopsy material will be collected and biobanked, and multiomics analyses will be conducted. ETHICS AND DISSEMINATION: The study will be conducted in compliance with this protocol and applicable national and international regulatory requirements. The study initiation package is submitted at the local level. The study protocol has been approved by local medical ethical committees in all 10 participating countries. Results will be made public and published in scientific, peer-reviewed, international journals and at international conferences. REGISTRATION DETAILS: NCT05651724, registration date: 15 Dec 2022.

• MeSH
• Diabetes Mellitus, Type 2 complications   MeSH
• Liver Cirrhosis diagnosis   MeSH
• Humans MeSH
• Metabolic Syndrome complications   MeSH
• Multicenter Studies as Topic MeSH
• Non-alcoholic Fatty Liver Disease * diagnosis   MeSH
• Mass Screening * methods   MeSH
• Prospective Studies MeSH
• Research Design MeSH
• Fatty Liver * diagnosis   epidemiology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial Protocol MeSH

OBJECTIVES: To assess the ability, as well as factors affecting the ability, of ultrasound examiners with different levels of ultrasound experience to detect correctly infiltration of ovarian cancer in predefined anatomical locations, and to evaluate the inter-rater agreement regarding the presence or absence of cancer infiltration, using preacquired ultrasound videoclips obtained in a selected patient sample with a high prevalence of cancer spread. METHODS: This study forms part of the Imaging Study in Advanced ovArian Cancer multicenter observational study (NCT03808792). Ultrasound videoclips showing assessment of infiltration of ovarian cancer were obtained by the principal investigator (an ultrasound expert, who did not participate in rating) at 19 predefined anatomical sites in the abdomen and pelvis, including five sites that, if infiltrated, would indicate tumor non-resectability. For each site, there were 10 videoclips showing cancer infiltration and 10 showing no cancer infiltration. The reference standard was either findings at surgery with histological confirmation or response to chemotherapy. For statistical analysis, the 19 sites were grouped into four anatomical regions: pelvis, middle abdomen, upper abdomen and lymph nodes. The videoclips were assessed by raters comprising both senior gynecologists (mainly self-trained expert ultrasound examiners who perform preoperative ultrasound assessment of ovarian cancer spread almost daily) and gynecologists who had undergone a minimum of 6 months' supervised training in the preoperative ultrasound assessment of ovarian cancer spread in a gynecological oncology center. The raters were classified as highly experienced or less experienced based on annual individual caseload and the number of years that they had been performing ultrasound evaluation of ovarian cancer spread. Raters were aware that for each site there would be 10 videoclips with and 10 without cancer infiltration. Each rater independently classified every videoclip as showing or not showing cancer infiltration and rated the image quality (on a scale from 0 to 10) and their diagnostic confidence (on a scale from 0 to 10). A generalized linear mixed model with random effects was used to estimate which factors (including level of experience, image quality, diagnostic confidence and anatomical region) affected the likelihood of a correct classification of cancer infiltration. We assessed the observed percentage of videoclips classified correctly, the expected percentage of videoclips classified correctly based on the generalized linear mixed model and inter-rater agreement (reliability) in classifying anatomical sites as being infiltrated by cancer. RESULTS: Twenty-five raters participated in the study, of whom 13 were highly experienced and 12 were less experienced. The observed percentage of correct classification of cancer infiltration ranged from 70% to 100% depending on rater and anatomical site, and the median percentage of correct classification for the 25 raters ranged from 90% to 100%. The probability of correct classification of all 380 videoclips ranged from 0.956 to 0.975 and was not affected by the rater's level of ultrasound experience. The likelihood of correct classification increased with increased image quality and diagnostic confidence and was affected by anatomical region. It was highest for sites in the pelvis, second highest for those in the middle abdomen, third highest for lymph nodes and lowest for sites in the upper abdomen. The inter-rater agreement of all 25 raters regarding the presence of cancer infiltration ranged from substantial (Fleiss kappa, 0.68 (95% CI, 0.66-0.71)) to very good (Fleiss kappa, 0.99 (95% CI, 0.97-1.00)) depending on the anatomical site. It was lowest for sites in the upper abdomen (Fleiss kappa, 0.68 (95% CI, 0.66-0.71) to 0.97 (95% CI, 0.94-0.99)) and highest for sites in the pelvis (Fleiss kappa, 0.94 (95% CI, 0.92-0.97) to 0.99 (95% CI, 0.97-1.00)). CONCLUSIONS: Ultrasound examiners with different levels of ultrasound experience can classify correctly predefined anatomical sites as being infiltrated or not infiltrated by ovarian cancer based on video recordings obtained by an experienced ultrasound examiner, and the inter-rater agreement is substantial. The likelihood of correct classification as well as the inter-rater agreement is highest for sites in the pelvis and lowest for sites in the upper abdomen. However, owing to the study design, our results regarding diagnostic accuracy and inter-rater agreement are likely to be overoptimistic. © 2025 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

• MeSH
• Video Recording MeSH
• Abdomen diagnostic imaging   pathology   MeSH
• Neoplasm Invasiveness diagnostic imaging   MeSH
• Clinical Competence * MeSH
• Middle Aged MeSH
• Humans MeSH
• Ovarian Neoplasms * diagnostic imaging   pathology   MeSH
• Observer Variation MeSH
• Pelvis diagnostic imaging   pathology   MeSH
• Prevalence MeSH
• Aged MeSH
• Ultrasonography methods   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Observational Study MeSH
• Research Support, Non-U.S. Gov't MeSH

Epilepsy, affecting over 50 million people globally, presents a significant neurological challenge. Effective prevention of epileptic seizures relies on proper administration and monitoring of Anti-Seizure Medication (ASMs). Therapeutic Drug Monitoring (TDM) ensures optimal dosage adjustment, minimizing adverse effects and potential drug interactions. While traditional venous blood collection for TDM may be stressful, emerging alternative sampling methods, particularly Dried Blood Spot (DBS) or oral fluid offer less invasive way of sampling. This study aimed to develop and validate an analytical method for the determination of lamotrigine in such alternative samples. The sample, either DBS or oral fluid, was subjected to extraction, evaporation, and reconstitution in 15 % acetonitrile containing 0.1 % formic acid. A Kinetex C18 Polar column was used for liquid chromatographic separation and MS in ESI+ mode was used for detection and quantitation of lamotrigine using an isotopically labelled internal standard according to EMA guidelines. The calibration range of the developed method enables the determination of lamotrigine in the concentration range of 1-30 μg/mL in DBS and 0.5-20 μg/mL in oral fluid. Oral fluid and DBS samples from patients treated with lamotrigine analysed by the developed method were compared to plasma concentrations measured by the hospital's accredited laboratory. Preliminary results indicate a promising potential for these alternative matrices in clinical TDM applications. By offering a less invasive sampling approach, this method improves the accessibility and safety of pharmacotherapy for epilepsy patients. The results of this study lay the foundation for further clinical applications by implementing alternative matrix TDM, which may significantly advance personalized care in epilepsy management.

• MeSH
• Anticonvulsants * analysis   blood   MeSH
• Chromatography, Liquid methods   MeSH
• Epilepsy drug therapy   MeSH
• Calibration MeSH
• Liquid Chromatography-Mass Spectrometry MeSH
• Lamotrigine * analysis   blood   MeSH
• Humans MeSH
• Limit of Detection MeSH
• Drug Monitoring * methods   MeSH
• Reproducibility of Results MeSH
• Saliva * chemistry   MeSH
• Tandem Mass Spectrometry methods   MeSH
• Dried Blood Spot Testing * methods   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Validation Study MeSH

BACKGROUND: The oncologic safety of minimally invasive simple hysterectomy in low-risk cervical cancer has not been explored by an adequately powered clinical trial. PRIMARY OBJECTIVE: This study aims to evaluate whether minimally invasive simple hysterectomy affects disease-free survival in low-risk early-stage cervical cancer. STUDY HYPOTHESIS: Minimally invasive simple hysterectomy represents an oncologically safe approach in selected patients with low-risk cervical cancer. TRIAL DESIGN: This is a single-arm trial with stopping rules. All patients must undergo cervical conization. Patients with clear conization margins or absence of residual macroscopic disease at imaging after conization (re-conization is mandatory if these criteria are not met) are submitted to minimally invasive (laparoscopy or robot-assisted laparoscopy) simple hysterectomy with sentinel lymph node biopsy algorithm. Adjuvant therapy is given in case of tumor-involved surgical margins, and/or metastatic lymph nodes, and/or substantial lymphovascular space invasion with depth of stromal infiltration >2/3 (or tumor-free distance ≤3 mm). MAJOR INCLUSION/EXCLUSION CRITERIA: The major inclusion criteria are: squamous cell carcinoma, human papillomavirus-related adenocarcinoma, adenosquamous carcinoma of the uterine cervix; International Federation of Gynecology and Obstetrics 2018 stage IA2-IB1 (≤2 cm) with depth of infiltration ≤10 mm on conization specimen; International Federation of Gynecology and Obstetrics 2018 stage IA2-IB1 (≤2 cm) with depth of infiltration ≤50% at pre-conization magnetic resonance imaging scan or "expert" ultrasound scan. Women are not eligible if they have evidence of metastatic disease, contra-indications to surgery and/or lymph node assessment, or fertility sparing desire. PRIMARY ENDPOINT: The primary end point is 3-year disease-free survival of patients who undergo minimally invasive simple hysterectomy. SAMPLE SIZE: A sample size of 974 patients will give a power of 80% at a significance level of 2.5% (1-sided) to reject the null hypothesis of a 3-year recurrence rate of 2.4%, assuming a 3-year recurrence rate of 1.2%. A maximum of 14 recurrences at 3 years should be observed to reject the null hypothesis. A stopping rule based on the number of recurrences observed at different timepoints will be implemented to avoid a higher recurrence rate with the study procedure. The trial will also be stopped if no recurrences are observed in the first 400 patients followed up for 2 years. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: The enrolment will last 60 months. After the surgery, the follow-up time will be ≥3 years. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (NCT06416748) and as ENGOT/MITO trial (ENGOT-cx23).

• MeSH
• Adult MeSH
• Hysterectomy * methods   MeSH
• Conization MeSH
• Laparoscopy methods   MeSH
• Middle Aged MeSH
• Humans MeSH
• Minimally Invasive Surgical Procedures methods   MeSH
• Uterine Cervical Neoplasms * surgery   pathology   MeSH
• Robotic Surgical Procedures methods   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial MeSH